Polypharmacy and Kidney Function in Community-Dwelling Adults Age 60 Years and Older: A Prospective Observational Study.

OBJECTIVES: Information on the impact of polypharmacy on kidney function in older adults is limited. We prospectively investigated the association between intake of total number of drugs or nonsteroidal anti-inflammatory drugs (NSAIDs) and kidney function. DESIGN: Our study is a prospective observational analysis of the 2-year Zurich Multiple Endpoint Vitamin D Trial in Knee Osteoarthritis Patients. SETTING AND PARTICIPANTS: Of the 273 participants of the original trial, 270 participants (mean age 70.3 ± 6.4 years, 53% women) were included in this observational analysis. METHODS: The associations between (1) total number of drugs (or NSAIDs) at baseline or (2) cumulative number of drugs (or NASAIDs) repeatedly measured over 24 months and kidney function repeatedly measured over 24 months as estimated glomerular filtration rate (eGFR) were investigated using multivariable-adjusted repeated-measures analysis. RESULTS: Per drug at baseline, kidney function decreased by 0.64 mL/min/1.73 m2 eGFR (Beta = -0.64; 95% CI -1.19 to -0.08; P = .024) over 24 months. With every additional drug taken cumulatively over 24 months, kidney function decreased by 0.39 mL/min/1.73 m2 eGFR (Beta = -0.39; 95% CI -0.63 to -0.15; P = .002). In a high-risk subgroup, per NSAID taken cumulatively over 24 months, kidney function declined by 1.21 mL/min/1.73 m2 eGFR (Beta = -1.21; 95% CI -2.35 to -0.07; P = .021). CONCLUSIONS AND IMPLICATIONS: For every additional drug prescribed among older adults, our study supports an independent and immediate harmful impact on kidney function. This negative impact seems to be about 3 times greater for NSAIDs compared with an additional average drug.

Shared Decision-Making Training in Internal Medicine: A Multisite Intervention Study.

BACKGROUND: Research shows that when patients and health care providers share responsibility for clinical decisions, both patient satisfaction and quality of care increase, and resource use decreases. Yet few studies have assessed how to train residents to use shared decision-making (SDM) in their practice. OBJECTIVE: We developed and evaluated a SDM training program in internal medicine. METHODS: Senior internal medicine residents from 3 hospitals in Switzerland were assessed shortly before and 2 months after completing a program that included a 2-hour workshop and pocket card use in clinical practice. Encounters with standardized patients (SPs) were recorded and SDM performance was assessed using a SDM completeness rating scale (scores ranging from 0 to 100), a self-reported questionnaire, and SPs rating the residents. RESULTS: Of 39 eligible residents, 27 (69%) participated. The mean (SD) score improved from 65 (SD 13) to 71 (SD 12; effect size [ES] 0.53; P = .011). After training, participants were more comfortable with their SDM-related knowledge (ES 1.42, P < .001) and skills (ES 0.91, P < .001), and with practicing SDM (ES 0.96, P < .001). Physicians applied SDM concepts more often in practice (ES 0.71, P = .001), and SPs felt more comfortable with how participants discussed their care (ES 0.44, P = .031). CONCLUSIONS: The SDM training program improved the competencies of internal medicine residents and promoted the use of SDM in clinical practice. The approach may be of interest for teaching SDM to residents in other disciplines and to medical students.

Transfusion practice in anemic, non-bleeding patients: Cross-sectional survey of physicians working in general internal medicine teaching hospitals in Switzerland.

BACKGROUND: Transfusion practice might significantly influence patient morbidity and mortality. Between European countries, transfusion practice of red blood cells (RBC) greatly differs. Only sparse data are available on transfusion practice of general internal medicine physicians in Switzerland. METHODS: In this cross-sectional survey, physicians working in general medicine teaching hospitals in Switzerland were investigated regarding their self-reported transfusion practice in anemic patients without acute bleeding. The definition of anemia, transfusion triggers, knowledge on RBC transfusion, and implementation of guidelines were assessed. RESULTS: 560 physicians of 71 hospitals (64%) responded to the survey. Anemia was defined at very diverging hemoglobin values (by 38% at a hemoglobin <130 g/L for men and by 57% at <120 g/L in non-pregnant women). 62% and 43% respectively, did not define anemia in men and in women according to the World Health Organization. Fifty percent reported not to transfuse RBC according to international guidelines. Following factors were indicated to influence the decision to transfuse: educational background of the physicians, geographical region of employment, severity of anemia, and presence of known coronary artery disease. 60% indicated that their knowledge on Transfusion-related Acute Lung Injury (TRALI) did not influence transfusion practice. 50% of physicians stated that no local transfusion guidelines exist and 84% supported the development of national recommendations on transfusion in non-acutely bleeding, anemic patients. CONCLUSION: This study highlights the lack of adherence to current transfusion guidelines in Switzerland. Identifying and subsequently correcting this deficit in knowledge translation may have a significant impact on patient care.

Efficacy and Safety of Long-Term Imatinib Therapy for Pulmonary Arterial Hypertension.

BACKGROUND: Antiproliferative strategies have emerged as a potential therapeutic option for pulmonary arterial hypertension (PAH). OBJECTIVE: To evaluate the long-term efficacy and safety of imatinib. METHODS: This is an observational study of 15 patients with idiopathic PAH (n = 13) or PAH associated with connective tissue disease (n = 2) treated off-label with imatinib 400 mg daily. Pulmonary hypertension-specific therapy was established in all patients (triple therapy in 10, dual therapy in 3, and monotherapy in 2 patients). RESULTS: After 6 months, improvement in hemodynamics (p < 0.01), functional class (p = 0.035), and quality of life (p = 0.005) was observed. After a median follow-up of 37 months, there was a sustained improvement in functional class (p = 0.032), quality of life (p = 0.019), and echocardiographic parameters of right ventricular function (p < 0.05). Three patients (20%) presented with completely normal echocardiography, absent tricuspid regurgitation, and normal pro-brain natriuretic peptide levels, indicative of 'hemodynamic remission'. Of note, however, only 1 case was assessed by invasive hemodynamics. The overall 1- and 3-year survival was 100 and 90%, respectively. Two patients experienced a subdural hematoma (SDH), which in both cases resolved without sequelae. After careful consultation of the potential risks and benefits, all patients as well as a safety cohort of 9 subsequent cases decided to continue the imatinib therapy. After adjusting the target international normalized ratio (INR) to around 2.0, no further cases of SDH occurred during 50 patient-years. CONCLUSIONS: Long-term treatment with imatinib may improve the functional class and quality of life. Single cases might even attain hemodynamic remission. The occurrence of 5% SDH per patient-years is concerning. However, adjusting the INR to around 2.0 might obviate this complication.

Reference values for the 6-minute walk test in healthy children and adolescents in Switzerland.

BACKGROUND: The six-minute walk test (6MWT) is a simple, low tech, safe and well established, self-paced assessment tool to quantify functional exercise capacity in adults. The definition of normal 6MWT in children is especially demanding since not only parameters like height, weight and ethnical background influence the measurement, but may be as crucial as age and the developmental stage. The aim of this study is establishing reference values for the 6MWT in healthy children and adolescents in Switzerland and to investigate the influence of age, anthropometrics, heart rate, blood pressure and physical activity on the distance walked. METHODS: Children and adolescents between 5-17 years performed a 6MWT. Short questionnaire assessments about their health state and physical activities. anthropometrics and vitals were measured before and after a 6-minute walk test and were previously defined as secondary outcomes. RESULTS: Age, height, weight and the heart rate after the 6MWT all predicted the distance walked according to different regression models: age was the best single predictor and mostly influenced walk distance in younger age, anthropometrics were more important in adolescents and females. Heart rate after the 6MWT was an important distance predictor in addition to age and outreached anthropometrics in the majority of subgroups assessed. CONCLUSIONS: The 6MWT in children and adolescents is feasible and practical. The 6MWT distance depends mainly on age; however, heart rate after the 6MWT, height and weight significantly add information and should be taken into account mainly in adolescents. Reference equations allow predicting 6-minute walk test distance and may help to better assess and compare outcomes in young patients with cardiovascular and respiratory diseases and are highly warranted for different populations.

Wrist actigraphy predicts outcome in patients with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) impairs quality of life, exercise performance and survival. Simple measures to monitor the disease are needed. OBJECTIVES: We tested whether actigraphy by a wrist-worn device in the patient's home reflects disease severity in PH patients. METHODS: Twenty-three outpatients with pulmonary arterial and chronic thromboembolic PH (15 females), functional classes II-IV, underwent clinical examination and actigraphy over 2 weeks while pursuing their usual life at home. Actigraphies were correlated with clinical data and mean pulmonary artery pressure (mPAP). Deaths, lung transplantations and pulmonary endarterectomy were recorded over 4 years. RESULTS: Actigraphies revealed a mean ± SD daytime activity duration of 14:57 ± 1:14 h with 146 ± 125 activity counts/min. Very severely impaired patients (mPAP 50 ± 7 mm Hg) were inactive for longer periods at night (8:25 ± 1:18 h) and less active during the day (54 ± 44 counts/min) when compared to modestly impaired patients (mPAP 33 ± 7 mm Hg; inactive at night for 6:58 ± 0:39 h; daytime activity 229 ± 148 counts/min, p < 0.05 in all instances). Out of 19 patients followed for 4 years, 5 died and 1 received a lung transplantation. Kaplan-Meier analysis revealed a shorter survival without lung transplantation in patients with a duration of daytime activity of <15 h/day than those with >15 h/day duration (log rank, p = 0.026). CONCLUSION: A long nocturnal rest and reduced daytime activity recorded by actigraphy are associated with severe hemodynamic impairment and reduced survival in patients with PH. Therefore, wrist actigraphy performed during everyday life in the patient's home holds promise as a simple tool for the assessment of disease severity and prognosis in patients with PH.

Lung function and breathing pattern in subjects developing high altitude pulmonary edema.

INTRODUCTION: The purpose of the study was to comprehensively evaluate physiologic changes associated with development of high altitude pulmonary edema (HAPE). We tested whether changes in pulmonary function and breathing pattern would herald clinically overt HAPE at an early stage. METHODS: In 18 mountaineers, spirometry, diffusing capacity, nitrogen washout, nocturnal ventilation and pulse oximetry were recorded at 490 m and during 3 days after rapid ascent to 4559 m. Findings were compared among subjects developing HAPE and those remaining well (controls). RESULTS: In 8 subjects subsequently developing radiographically documented HAPE at 4559 m, median FVC declined to 82% of low altitude baseline while closing volume increased to 164% of baseline (P<0.05, both instances). In 10 controls, FVC decreased slightly (to 93% baseline, P<0.05) but significantly less than in subjects with HAPE and closing volume remained unchanged. Sniff nasal pressure was reduced in both subjects with and without subsequent HAPE. During nights at 4559 m, mean nocturnal oxygen saturation dropped to lower values while minute ventilation, the number of periodic breathing cycles and heart rate were higher (60%; 8.6 L/min; 97 cycles/h; 94 beats/min, respectively) in subjects subsequently developing HAPE than in controls (73%; 5.1 L/min; 48 cycles/h; 79 beats/min; P<0.05 vs. HAPE, all instances). CONCLUSION: The results comprehensively represent the pattern of physiologic alterations that precede overt HAPE. The changes in lung function are consistent with reduced lung compliance and impaired gas exchange. Pronounced nocturnal hypoxemia, ventilatory control instability and sympathetic stimulation are further signs of subsequent overt HAPE.

Pulmonary hypertension in patients with Martorell hypertensive leg ulcer: a case control study.

BACKGROUND: Martorell hypertensive ischemic leg ulcer (Martorell ulcer) is characterized by distinct alterations in the arteriolar wall of subcutaneous vessels, leading to progressive narrowing of the vascular lumen and increase of vascular resistance. These changes are similar to the alterations observed in pulmonary arterioles in patients with chronic pulmonary hypertension (PH). This study was aimed to assess an association between the two disorders. METHODS: In this case-control study, 14 patients with Martorell ulcer were clinically assessed for the presence of pulmonary hypertension using transthoracic Doppler echocardiography. Data from patients were compared to 28 matched hypertensive controls. RESULTS: Systolic pulmonary arterial pressure (sPAP) in patients with Martorell ulcer was significantly higher than in the control group (33.8 ± 16.9 vs 25.3 ± 6.5 mmHg, p = 0.023); the prevalence of pulmonary hypertension was 31% (5/14) in patients and 7% (2/28) in controls (p = 0.031). No differences were seen in left heart size and function between patients and controls. CONCLUSION: This study provides first evidence that subcutaneous arteriolosclerosis, the hallmark of Martorell ulcer, is associated with PH. These findings suggest that patients with Martorell leg ulcer might be at significant risk to develop elevated pulmonary arterial pressure. Patients with leg ulcers who present with dyspnea should be evaluated by echocardiography for the presence of pulmonary hypertension.

Platelet serotonin content and transpulmonary platelet serotonin gradient in patients with pulmonary hypertension.

BACKGROUND: The serotonin system has repeatedly been associated with the pathogenesis of pulmonary hypertension (PH). OBJECTIVE: To comparatively analyze plasmatic and intrathrombocytic serotonin levels in arterial and mixed venous blood of patients with PH and unaffected controls to elucidate pulmonary serotonin metabolisms. PATIENTS AND METHODS: Catheters were placed in the radial and pulmonary artery in patients with PH (n = 13) for diagnosis and in age-matched controls (n = 6) undergoing percutaneous closure of the patent foramen ovale. Arterial and mixed venous blood samples were immediately centrifuged to obtain plasma and platelets and thereafter frozen at -20°C. After careful thawing, plasmatic and platelet serotonin levels were determined by ELISA. RESULTS: PH was classified as arterial in 4 and chronic thromboembolic in 9 patients with a mean pulmonary artery pressure of 37 (interquartile range: 32-43) mm Hg. Platelet serotonin content was significantly lower in the PH patients than in the controls. The mean transpulmonary gradient (arterial-mixed venous) was negative in the PH group and positive in the controls. An inverse correlation was found between the arterial blood platelet serotonin content and pulmonary hemodynamics. Plasmatic serotonin levels did not differ between the PH and control groups. CONCLUSION: The lower platelet serotonin concentration in PH patients compared with unaffected controls is an unprecedented finding. The negative transpulmonary platelet serotonin gradient and the strong negative correlation of arterial blood platelet serotonin with pulmonary hemodynamics might indicate increased serotonin uptake in the lungs of PH patients.

Tobacco smoke: a risk factor for pulmonary arterial hypertension? A case-control study.

BACKGROUND: Smoking is a well-known risk factor for cardiovascular, lung, and many other diseases. Smoking can induce pulmonary arterial hypertension (PAH) in animal models; PAH is common in smokers with COPD and thereby not correlated with the degree of airway obstruction. The impact of tobacco smoke exposure on the development of PAH in humans is not known. METHODS: In a case-control study we assessed smoking and secondhand smoke exposure in all patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH) seen at our pulmonary hypertension clinic from 2002 until July 2008. Data from patients with PAH were compared with CTEPH and healthy control subjects from the Swiss Health Survey 2007. RESULTS: Ninety-one patients with PAH were compared with 64 patients with CTEPH and 18,747 control subjects (women 58, 36, 10,331, respectively). Tobacco smoking was significantly more common in PAH compared with CTEPH and control subjects. This difference could be attributed to men. Patients with PAH also smoked longer and more heavily compared with patients with CTEPH. In addition, secondhand smoke exposure was significantly longer in nonsmokers with PAH compared with control subjects. CONCLUSION: Our data indicate that tobacco smoke exposure may be a risk factor for men with PAH. Considering smoking as a risk factor for PAH will have implications in counseling patients and especially their hitherto unaffected relatives. Further research on the pathogenetic role of smoking in PAH is warranted.

Sequence variants in BMPR2 and genes involved in the serotonin and nitric oxide pathways in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: relation to clinical parameters and comparison with left heart disease.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH) share important pathogenic and clinical features. BMPR2 mutations are important in the pathogenesis of IPAH, but little is known about the genetic background in CTEPH. OBJECTIVE: To search for mutations and polymorphisms in genes involved in the BMPR2, serotonin and nitric oxide pathways possibly associated with pulmonary and cardiac disorders in IPAH and CTEPH. METHODS: In a cohort of Swiss patients with IPAH (n = 16) and CTEPH (n = 16), and in 24 controls with left heart disease without PH, polymorphisms in the BMPR2, 5-HHT, 5-HTR-2A and eNOS genes were analyzed and correlated with various clinical, functional and hemodynamic parameters. RESULTS: We found a BMPR2 missense mutation in a patient with coronary artery disease (CAD) without PH but no BMPR2 mutations in our collective with late-onset sporadic PH. In patients with polymorphic variants of the BMPR2 gene, the number of blood platelets and oxygen saturation were increased. The c.600A-->C synonymous variant was associated with worse exercise capacity and decreased quality of life in PH. We found no significant differences for any measured parameter according to the eNOS, 5-HTR2A and the 5-HTT polymorphisms, although there was a higher allelic frequency of the 5-HTT long variant in IPAH than in CTEPH and controls. CONCLUSION: Our first report of a BMPR2 mutation in a patient with CAD without PH is interesting and warrants further investigation. Our study may reflect the clinical status and genetic background in a typical PH cohort as seen in a single tertiary care referral center.

Genetic polymorphisms of the serotonin transporter, but not the 2a receptor or nitric oxide synthetase, are associated with pulmonary hypertension in chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary hypertension (PH) is prognosti- cally important in chronic obstructive pulmonary disease (COPD). Since PH only weakly correlates with hypoxemia, other factors must play a role. OBJECTIVE: To investigate whether polymorphisms of the serotonin transporter (5HTT), serotonin-2a receptor (5HTR2a) and endothelial nitric oxide synthetase (eNOS) are related to PH in COPD. METHODS: In 59 COPD patients who underwent right heart catheterization, 6-min walking distance, NYHA functional class, pulmonary function tests, blood gases and 5HTT, 5HTR2a and eNOS (4ab and T298C) polymorphisms were determined. RESULTS: Forty-nine COPD patients in NYHA functional class III-IV were included. Ten were excluded due to comorbid causes of PH (mainly chronic thromboembolic). PH (mPAP > or =25 mm Hg) was present in 55% and usually mild, but out of proportion (mPAP > or =40 mm Hg) in 12%. Patients with PH had significantly higher frequencies of the 5HTT-L-allele (52%) compared to individuals without PH (36%), and LL homozygote patients had more severe PH. In patients with out-of-proportion PH, the L-allelic frequency was even 75%. We found no association of 5HTR2a and eNOS polymorphism with PH in COPD. CONCLUSIONS: In this COPD cohort we confirm that PH is frequent and usually mild, but out of proportion in a subgroup. We found a significant association of the L-allelic variant of 5HTT with PH overall and especially in out-of-proportion PH. These findings may point towards a role of the serotonin system in COPD-PH and warrant further studies.

Successful pregnancy in pulmonary arterial hypertension associated with systemic lupus erythematosus: a case report.

INTRODUCTION: Pulmonary arterial hypertension is a complication of systemic lupus erythematosus. Mortality in pregnant patients with pulmonary arterial hypertension related to connective tissue disease is as high as 56%. The authors report the first case of a successful maternal-fetal outcome in a pregnant patient with systemic lupus erythematosus-associated pulmonary arterial hypertension treated with sildenafil and inhaled iloprost during pregnancy and until several weeks after caesarean section. CASE PRESENTATION: The case presented is of a 29-year-old woman with systemic lupus erythematosus and associated severe pulmonary arterial hypertension. Vasodilator therapy with bosentan and sildenafil, immunosuppressive therapy with prednisone, hydroxychloroquine and azathioprine and oral anticoagulation (phenprocoumon) had normalized her right ventricular over right atrial pressure when she was diagnosed in her 5th week of pregnancy. The teratogenic drugs bosentan and phenprocoumon were stopped, the latter replaced by low molecular weight heparin. During the 35th week, a slight increase in pulmonary pressure was found. Therapy with inhaled iloprost was established. A caesarean section was performed in the 37th week and a healthy baby was delivered. The patient remained stable until 11 weeks after delivery, when an increase in right ventricular over right atrial pressure was noted. Bosentan was reintroduced and prednisone and azathioprine doses were increased. The patient has remained stable until the present time. CONCLUSION: Pulmonary arterial hypertension has been considered a contraindication for pregnancy. Novel vasodilator therapy, combined with immunosuppressants in this patient with systemic lupus erythematosus, may "cure" pulmonary arterial hypertension and permit pregnancy with successful outcome. However, postpartum exacerbation of systemic lupus erythematosus and pulmonary arterial hypertension have to be considered.

Caveolin-1 Expression and Hemodynamics in COPD Patients.

Caveolin-1 is a regulator of both intracellular calcium homeostasis and endothelial nitric oxide synthase and may play a pathogenetic role in pulmonary hypertension. In the present study, we aimed to investigate the correlations between pulmonary hemodynamics and vessel morphology including the expression of Caveolin-1 in pulmonary arterioles from patients with chronic obstructive pulmonary disease (COPD) who underwent lung-volume reduction surgery. Staining and subsequent analysis was performed on paraffin-embedded lung tissue from COPD patients (n = 12). Pulmonary arteries with an external diameter of 100-500microm were analysed. Immunhistochemistry with antibodies against caveolin-1 was performed and intensity was assessed. Morphometric data were obtained by using computer-assisted imaging software. The findings were quantified and correlated to hemodynamic data obtained by right-heart catheterization. In COPD patients with pulmonary hypertension (n = 5), the expression of caveolin-1 within the medial smooth muscle cell layer was found to be increased, whereas the intimal caveolin-1 was more prominently expressed in COPD patients with normal pulmonary pressures (n = 7). The ratio between these expression patterns was positively correlated to the mean pulmonary artery pressure. Similar findings were observed for the ratio between intimal and medial thickness as well as for the expression of smooth muscle actin (SMA).Taken together, the expression of caveolin-1 within medial smooth muscle cells of pulmonary arteries in patients with COPD is associated with pulmonary hypertension. Our results thus emphasize a potential novel player in the pathogenesis of COPD-associated pulmonary hypertension.

Dexamethasone but not tadalafil improves exercise capacity in adults prone to high-altitude pulmonary edema.

RATIONALE: Whether pulmonary hypertension at high altitude limits exercise capacity remains uncertain. OBJECTIVES: To gain further insight into the pathophysiology of hypoxia induced pulmonary hypertension and the resulting reduction in exercise capacity, we investigated if the reduction in hypoxic pulmonary vasoconstrictive response with corticosteroids or phosphodiesterase-5 inhibition improves exercise capacity. METHODS: A cardiopulmonary exercise test and echocardiography to estimate systolic pulmonary artery pressure were performed in 23 subjects with previous history of high altitude pulmonary edema, known to be associated with enhanced hypoxic vasoconstriction. Subjects were randomized to dexamethasone 8 mg twice a day, tadalafil 10 mg twice a day, or placebo (double-blinded), starting the day before ascent. MEASUREMENTS AND MAIN RESULTS: Measurements were performed at low and high (i.e., 4,559 m) altitude. Altitude exposure decreased maximum oxygen uptake and oxygen saturation, increased pulmonary artery pressure, and altered oxygen uptake kinetics. Compared with placebo, dexamethasone improved maximum oxygen uptake (% predicted 74 +/- 13%; tadalafil 63 +/- 13%, placebo 61 +/- 11%; P < 0.05), oxygen kinetics (mean response time 41 +/- 13 s; tadalafil 46 +/- 6 s, placebo 45 +/- 10 s; P < 0.05), and reduced the ventilatory equivalent for CO(2) (42 +/- 4; tadalafil 49 +/- 4, placebo 50 +/- 5; P < 0.01). Peak oxygen saturation did not differ significantly between the three groups (dexamethasone 66 +/- 7%, placebo 62 +/- 7%, tadalafil 69 +/- 5%; P = 0.08). During echocardiography at low-intensity exercise (40% of peak power), dexamethasone compared with placebo resulted in lower pulmonary artery pressure (47 +/- 9 mm Hg; tadalafil 57 +/- 11 mm Hg, placebo 68 +/- 23 mm Hg; P = 0.05) and higher oxygen saturation (74 +/- 7%; tadalafil 67 +/- 3%, placebo 61 +/- 20; P < 0.02). CONCLUSIONS: Corticosteroids, but not phosphodiesterase-5 inhibition, partially prevented the limitation of exercise capacity in subjects with intense hypoxic pulmonary vasoconstriction at high altitude.

Bone mineral density and secondary hyperparathyroidism in pulmonary hypertension.

BACKGROUND: Low bone mineral density (BMD) is common in chronic lung diseases and associated with reduced quality of life. Little is known about BMD in pulmonary hypertension (PH). METHODS: Steroid-naïve patients with PH (n=34; 19 idiopathic, 15 chronic thromboembolic) had BMD measured by DXA at the time of diagnostic right heart catheterization. Exercise capacity, quality of life and various parameters related to PH severity and bone metabolism were also assessed. 24 patients with left heart failure (LHF) were similarly assessed as controls. RESULTS: The prevalence of osteopenia was high both in PH (80%) and in controls with LHF (75%). Low BMD was associated with lean body mass, age, lower BMI, impaired exercise capacity and in PH with higher pulmonary vascular resistance. Serum parathyroid hormone (PTH) was elevated and considerably higher in PH than in LHF (above normal, in 55 vs 29%). Secondary hyperparathyroidism was not related to impaired renal function but possibly to low vitamin D status. CONCLUSIONS: Osteopenia is common in PH and in chronically ill patients with LHF. Osteopenia is associated with known risk factors but in PH also with disease severity. Preventive measures in an increasingly chronic ill PH population should be considered. Secondary hyperparathyroidism is highly prevalent in PH and might contribute to bone and possibly pulmonary vascular disease. Whether adequate vitamin D substitution could prevent low BMD in PH remains to be determined.

Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway.

Dysregulated expression of bone morphogenetic protein receptor type II (BMPR2) is a pathogenetic hallmark of pulmonary hypertension. Downregulation of BMPR2 protein but not mRNA has been observed in multiple animal models mimicking the disease, indicating a posttranscriptional mechanism of regulation. Because microRNAs (miRNAs) regulate gene expression mainly through inhibition of target gene translation, we hypothesized that miRNAs may play a role in the modulation of BMPR2. Performing a computational algorithm on the BMPR2 gene, several miRNAs encoded by the miRNA cluster 17/92 (miR-17/92) were retrieved as potential regulators. Ectopic overexpression of miR-17/92 resulted in a strong reduction of the BMPR2 protein, and a reporter gene system showed that BMPR2 is directly targeted by miR-17-5p and miR-20a. By stimulation experiments, we found that the miR-17/92 cluster is modulated by interleukin (IL)-6, a cytokine involved in the pathogenesis of pulmonary hypertension. Because IL-6 signaling is mainly mediated by STAT3 (signal transducer and activator of transcription 3), the expression of STAT3 was knocked down by small interfering RNA, which abolished the IL-6-mediated expression of miR-17/92. Consistent with these data, we found a highly conserved STAT3-binding site in the promoter region of the miR-17/92 gene (C13orf25). Promoter studies confirmed that IL-6 enhances transcription of C13orf25 through this distinct region. Finally, we showed that persistent activation of STAT3 leads to repressed protein expression of BMPR2. Taken together, we describe here a novel STAT3-miR-17/92-BMPR2 pathway, thus providing a mechanistic explanation for the loss of BMPR2 in the development of pulmonary hypertension.

Pulmonary hypertension in Switzerland: treatment and clinical course.

BACKGROUND: The prognosis of pulmonary hypertension (PH), especially idiopathic pulmonary arterial hypertension (IPAH), has improved during the recent years. The Swiss Registry for PH represents the collaboration of the various centres in Switzerland dealing with PH and serves as an important tool in quality control. The objective of the study was to describe the treatment and clinical course of this orphan disease in Switzerland. METHODS: We analyzed data from 222 of 252 adult patients, who were included in the registry between January 1999 and December 2004 and suffered from either PAH, PH associated with lung diseases or chronic thromboembolic PH (CTEPH) with respect to the following data: NYHA class, six-minute walking distance (6-MWD), haemodynamics, treatments and survival. RESULTS: If compared with the calculated expected figures the one, two and three year mean survivals in IPAH increased from 67% to 89%, from 55% to 78% and from 46% to 73%, respectively. Most patients (90%) were on oral or inhaled therapy and only 10 patients necessitated lung transplantation. Even though pulmonary endarterectomy (PEA) was performed in only 7 patients during this time, the survival in our CTEPH cohort improved compared with literature data and seems to approach outcomes usually seen after PEA. The 6-MWD increased maximally by 52 m and 59 m in IPAH and CTEPH, respectively, but in the long term returned to or below baseline values, despite the increasing use of multiple specific drugs (overall in 51% of IPAH and 29% of CTEPH). CONCLUSION: Our national registry data indicate that the overall survival of IPAH and presumably CTEPH seems to have improved in Switzerland. Although the 6-MWD improved transiently, it decreased in the long term despite specific and increasingly combined drug treatment. Our findings herewith underscore the progressive nature of the diseases and the need for further intense research in the field.

Human F(ab')2-containing immune complexes together with anti-hinge natural antibodies stimulate complement amplification in vitro and in vivo.

The systemic inflammatory response syndrome (SIRS) is triggered by C5a generation following an excessive complement amplification, but it has remained unclear how complement amplification is stimulated. It is known that neutrophilic elastase can cleave IgG to F(ab')(2) and that F(ab')(2)-containing immune complexes (F(ab')(2)-IC) stimulate complement amplification together with an unidentified plasma factor. We show that absorption of plasma on F(ab')(2) from human IgG removed this factor and prevented F(ab')(2)-IC from stimulating complement amplification. The required factor was purified from pooled whole human IgG (IVIG) as those naturally occurring antibodies (NAbs) that bind to F(ab')(2), but not to intact IgG. These "anti-hinge NAbs" restored complement amplification by F(ab')(2)-IC in absorbed plasma. Anti-hinge NAbs must have formed secondary, rigidified IC from F(ab')(2)-IC, because the F(ab')(2) fragments evidently captured dimeric C3b, known as a potent C3 convertase precursor. This process may also stimulate complement amplification in vivo, because plasma from septic patients at the onset of SIRS indeed contained F(ab')(2) fragments. The concentrations of F(ab')(2) and that of factor Bb, an unbiased measure of complement amplification, correlated linearly with that of released elastase. Moreover, the F(ab')(2) fragments migrated on gelfiltration columns together with anti-hinge NAbs as ICs with MW of up to approximately 750kDa, as verified on plasma of each of the nine patients studied. These findings provide for the first time a plausible mechanism of how F(ab')(2)-containing immune complexes stimulate complement amplification together with anti-hinge NAbs. The same mechanism may contribute to complement overreaction at the onset of SIRS.

Sleep-related breathing disorders in patients with pulmonary hypertension.

BACKGROUND: Cheyne-Stokes respiration (CSR) and central sleep apnea (CSA) are common in patients with left-heart failure. We investigated the hypothesis that sleep-disordered breathing is also prevalent in patients with right ventricular dysfunction due to pulmonary hypertension (PH). METHODS: We studied 38 outpatients (median age, 61 years; quartiles, 51 to 72) with pulmonary arterial hypertension (n = 23) or chronic thromboembolic PH (n = 15). New York Heart Association (NYHA) class was II to IV, and median 6-min walk distance was 481 m (quartiles, 429 to 550). In-laboratory polysomnography (n = 22) and ambulatory cardiorespiratory sleep studies (n = 38) including pulse oximetry were performed. Quality of life and sleepiness by the Epworth sleepiness score were assessed. RESULTS: The median apnea/hypopnea index was 8 events/h (quartiles, 4 to 19), with 8 central events (quartiles, 4 to 17), and 0 obstructive events (quartiles, 0 to 0.3) per hour. Seventeen patients (45%) had > or = 10 apnea/hypopnea events/h. Comparison of 13 patients with > or = 10 CSR/CSA events/h with 21 patients with < 10 CSR/CSA events/h (excluding 4 patients with > or = 10 obstructive events/h from this analysis) revealed no difference in regard to hemodynamics, NYHA class, and Epworth sleepiness scores. However, patients with > or = 10 CSR/CSA events/h had a reduced quality of life in the physical domains. Ambulatory cardiorespiratory sleep studies accurately predicted > or = 10 apnea/hypopnea events/h during polysomnography in patients who underwent both studies (area under the receiver operating characteristic curve, 0.93; SE +/- 0.06; p = 0.002). The corresponding value for pulse oximetry was 0.63 +/- 0.14 (p = not significant). CONCLUSIONS: In patients with PH, CSR/CSA is common, but obstructive sleep apnea also occurs. Sleep-related breathing disorders are not associated with excessive sleepiness but affect quality of life. They should be evaluated by polysomnography or cardiorespiratory sleep studies because pulse oximetry may fail to detect significant sleep apnea.